1. Field of the Invention
This invention relates to processes for preparing terfenadine and derivatives thereof. In another aspect this invention relates to processes for preparing terfenadine carboxylate. In another aspect this invention relates to synthetic intermediates.
2. Description of the Related Art
Terfenadine (Formula T) is a non-sedating antihistamine sold in the U.S. under the designation "Seldane" (Hoechst Marion Roussel). ##STR3## Certain derivatives of terfenadine are also known and disclosed as active antihistamines, e.g., in U.S. Pat. No. 4,254,129 (Carr et al.) The primary active metabolite of terfenadine is a compound known as terfenadine carboxylate or fexofenadine (Formula B), which is among the terfenadine derivatives disclosed in U.S. Pat. No. 4,254,129. The hydrochloride salt of terfenadine carboxylate is sold in the U.S. under the designation "Allegra" (Hoechst Marion Roussel). ##STR4##
Several synthetic methods for preparing terfenadine and derivatives thereof have been disclosed. For example, Carr et al. disclose a method involving acylation of a compound of Formula C and further elaboration to provide terfenadine carboxylate. ##STR5## The acylation step in this method, however, is said in International Patent Application No. WO 95/00482 (D'Ambra) to provide a mixture of regioisomers that includes the 3-substituted product in addition to the desired 4-substituted product. D'Ambra provides substantially pure regioisomers, e.g., through fractional crystallization of the acylation product. Regiochemically pure 4-substituted product for use in preparing terfenadine and derivatives can also be produced using a metal-mediated coupling approach, as described in J. Org. Chem. 1994, 59, 2620 (Kawai et al.), where 3-butyn-1-ol is coupled to methyl 2-(4-halophenyl)-2,2-dimethylacetate.
The process of the invention described below exhibits at least two major advantages over the processes of the art: (1) It is regiospecific; the manipulative complications that arise from the presence of multiple isomers are avoided. (2) The yield from aldehyde to final product is very much higher than known processes--59% overall.